The RB69 DNA polymerase binding-pocket residue Tyr567 was shown previously to be a key determinant of fidelity because the replacement Y567A causes a powerful mutator activity. Ser565 is a nearby component of the binding pocket. Unlike Y567A, the replacement S565G has only a small impact on fidelity. However, combining Y567A and S565G reverses most of the mutator activity of Y567A. This is a unique and instructive observation in structural studies of polymerase fidelity, and we have completed a detailed examination of the mutational propensities of these constructs both in vivo and in vitro. Combined with structural information about the mutant polymerases developed by another group, we now have an understanding of how fidelity is restored in the double mutant.